DESCRIPTION: (Applicant's Abstract) The objective of this work is to determine the importance of human polymorphic cytochrome P450 CYP2D6, CYP2A6 and CYP2C19 drug metabolizing enzymes in drug abuse and dependence. We hypothesize that the genetically variable CYP2D6, CYP2A6 and CYP2C19 resulting in "extensive metabolizers" (EM) and "poor metabolizers" (PM) of some drugs of abuse (e.g. codeine, methamphetamine, nicotine, flunitrazepam, diazepam) can be a risk- or protection-factor in drug dependence, depending on the activity of the parent drug and its metabolites. Since the frequency of the PM state is variable across ethnic groups (e.g. 10% of Caucasians and < 2% of Asians lack CYP2D6; 16% of Asians and < 2% of Caucasians lack CYP2C19 activity) differences observed in drug abuse patterns and toxicity may be based in part, on these pharmacogenetic polymorphisms. Since these CYP are found in the brain they may alter localized drug concentrations and account for differences in plasma drug concentration and drug effects and/or may play a neuromodulatory role in the brain. In human studies we will: 1) compare CYP allele frequencies in males and females of not drug-dependent and drug-using Caucasians, Asians and Canadian Indians and investigate the potential impact of genotype and CYP activity differences on drug taking behaviour and risk; 2) determine the impact of CYP2D6, CYP2A6 and CYP2C19 (genotype, allelic variants, phenotype and inhibition) on the metabolism and pharmacologic effects of methamphetamine, nicotine, flunitrazepam and diazepam; and 3) identify how CYP2D6 and CYP2A6 activity contributes to risk of dependence on codeine and nicotine. These studies will contribute to our understanding of the pharmacogenetic contribution to drug abuse and dependence and will help to develop new treatment and prevention approaches. In pre-clinical studies we plan to: 1) identify and characterize drugs of abuse that are substrates or inhibitors CYP2D6, CYP2A6 and CYP2C19 and their allelic variants; 2) define and compare the localization, catalytic activity and regulation of CYP2D6, CYP2A6 and CYP2C19 in monkey and human brain; and 3) using animal models, including inhibition of central CYP expression, to determine the importance of brain and peripheral activity to the toxicity and behavioural consequences of codeine, amphetamines and benzodiazepines.